The field of the invention relates to new small molecules and uses of the small molecules for inhibiting expression of superoxide dismutase (SOD) and treating diseases and disorders characterized by aberrant SOD activity or expression.
Superoxide dismutases (SOD)(EC 1.15.1.1) are enzymes that catalyze the dismutation of dioxide radicals (O2−) into oxide and hydrogen peroxide. As such, SODs provide an antioxidant defense in cells exposed to oxygen. Three forms of SODs are found in humans and in other mammals: SOD1, which is cytoplasmic; SOD2, which is mitochondrial; and SOD3, which is extracellular. SOD1 and SOD3 contain copper (Cu) and Zinc (Zn) in their reactive centers and are sometimes referred to as Cu,Zn-SODs. SOD2 contains manganese (Mn) in its reactive center and sometimes is referred to as Mn-SOD.
The SOD family of enzymes have been linked to a variety of diseases and disorders. (See, e.g., Noor et al., Med. Sci. Monit. 2002; 8(9):RA210-215; and Macmillan-Crow et al., Free Radic. Res. 2001 April; 34(4):325-36; the contents of which are incorporated herein by reference in their entireties). In particular, mutations in the SOD1 gene have been linked with familial amyotrophic lateral sclerosis (ALS), which is a degenerative motor neuron disease. Some mutations in SOD1 induce a toxic gain of function that is associated with the formation of protein aggregates as in ALS. (See, e.g., Milani et al. (2011) Neurol Res Int. 2011: 458427. doi:10.1155/2011/458427; Deng et al., (August 1993) Science. 261 (5124): 1047-51; Conwit R A (December 2006) J. Neurol. Sci. 251 (1-2): 1-2; and Leigh et al. (August 2000), Current Opinion in Neurology 13 (4): 397-405. doi:10.1097/00019052-200008000-00006; the contents of which are incorporated herein by reference in their entireties). Because some mutant forms of SOD1 induce a toxic gain of function associated with formation of protein aggregates in ALS, inhibition of expression of these mutant forms of SOD1 for treating ALS currently is a pharmacological target in current clinical trials. (See Lange, Amyotrophic. Lateral. Scler. 9[Suppl. 1], 45-47, 2008; and Smith et al., J. Clin. Invest. 116, 2290-2296, 2006). However, some inhibitors of SOD1 expression exhibit cell toxicity at effective concentrations and new inhibitors of SOD1 expression are desirable, in particular, small molecule inhibitors of superoxide dismutase expression.